Synthesis of New Analogues of the Tetraponerines

Abstract

To evaluate the influences of the tetraponerine alkyl chains and tricyclic ring systems on their cytotoxic activities, we have prepared a series of alkyl derivatives (3a, 3b and 4a–f) of the non‐natural tricyclic skeletons decahydro‐2H,6H‐dipyrido[1,2‐a:1′,2′‐c]pyrimidine (3, 6–6–6 skeleton) and dodecahydro‐2H‐1,8a‐diazaphenanthrene (4, iso‐6–6–6 skeleton). In this study, two ways to synthesise the 6–6–6 analogues have been developed and compared. One is based on the condensation of α‐tripiperideine with diethyl malonate (DEM) in water at pH 11. This yielded oxo ester 11, precursor of the amino nitrile 8, but only in moderate yield. In the second pathway, the key intermediate 8 was more efficiently synthesised by starting from 2‐(2‐piperidyl)ethanol. Treatment of 8 with alkyl Grignard reagents led to the 6–6–6 analogues 3a and 3b. When the one‐pot reaction between α‐tripiperideine and DEM was performed in water at pH 8, the lactam 12, precursor of the iso‐6–6–6 skeleton, was obtained in a yield of 76 %. The same lactam was also obtained in a yield of 86 % by treatment of tetrahydroanabasine 14 with DEM in water at pH 8. Lactam 12 was transformed into the iso‐6–6–6 analogues 4a–4f. The cytotoxic activities of the 6–6–6 and iso‐6–6–6 analogues against HT29 cancer cells were compared with those of the 5–6–5 and 6–6–5 tetraponerines and with those of solenopsin analogues. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Natural Tetraponerines: A General Synthesis and Antiproliferative Activity

“…6 In this study we have found that the antiproliferative activity of (+)-T7 is consistently bigger than that of (+)-T8 against another three different human cell lines. Biological procedures: Procedures used for biological assays are described in the Supporting Information.…”

“…Among the few studies accomplished, an assessment of the anticancer activity of some natural tetraponerines and their analogues against HT-29 cell line (colorectal carcinoma), showed that the larger hydrocarbonated chain at the C 5 , the lower IC 50 values were obtained. 6 With this precedents we decided to evaluate the cytoxicity of pentyl-side-chain tetraponerines ((+)−T5 to (+)−T8) at 4 different human carcinoma cell lines from different origins (A2780 from ovary carcinoma, NCI-H460 from lung, Caco-2 from colon and MCF-7 from breast). In order to predict the therapeutic range, we also screened these compounds over a non-tumoral cell line (MRC-5, lung fibroblasts).…”

Racemic synthesis of 2′‐substituted nicotine analogs

“…Its condensation with 5 equiv of 3-pyridylmagnesium bromide was attempted in THF at 0 C, followed by rt and in some cases by heating to reflux. However, the Bruylants reaction did not take place and 2 0 -methylnicotine was never obtained [22][23][24]. It only resulted in recovered starting material.…”

“…Replacement of this cyano group with an alkyl substituent was accomplished by a Bruylants reaction with an organomagnesium compound [22][23][24]. Displacement of the cyano group leads to an intermediate, stabilized iminium carbocation, which reacts further with the nucleophile alkyl organomagnesium (Scheme 4).…”

A New and Efficient Synthesis of Derivatives of Octahydro‐4H‐pyrrolo[1,2‐c]pyrido[1′,2′‐a]imidazole

“…Under these conditions, l-lysine is transformed into 5-aminopentanal, which cyclizes spontaneously into Δ 1 -piperideine. [8] When we treated a solution of Δ 1 -piperideine, prepared according to this method, with diethyl malonate (DEM) in the hope of forming 6-6-6 or iso-6-6-6 intermediates as described previously, [5] we observed consistent formation of the unexpected tricyclic product 6 (5-5-6 skeleton) in moderate yields (best yield 26 %) together with polymeric material. Despite numerous assays, which were carried out at various pH and various proportions of reactants, we never isolated 6-6-6 or iso-6-6-6 derivatives under these conditions.…”